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Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
Liu Changshui1,2; Zang Kun1,2,3; Li Shihao1,2,3,4; Li Fuhua1,2,3,4; Ma Qingiun1,2,3,4
2020-02-15
Source PublicationJOURNAL OF OCEANOLOGY AND LIMNOLOGY
ISSN2096-5508
Pages9
Corresponding AuthorMa Qingiun(qma@qdio.ac.cn)
AbstractThymidylate synthase (TS) is a key enzyme in the de novo biosynthesis of thymidine monophosphate, serving as a well-known drug target in chemotherapy against cancers and infectious diseases. Additional to its clinical value, TS is supposed to be a promising drug target in aquatic-disease control. To facilitate designing pathogen-specific TS inhibitors for shrimp-disease control, we report the crystal structures of TS from Litopenaeus vannamei (LvTS) in the apo form, LvTS-dUMP complex and LvTS-dUMP-raltitrexed complex at 2.27 A, 1.54 A, and 1.56 A resolution, respectively. LvTS shares a similar fold with known TSs, existing as a dimer in the crystal. The apo LvTS and LvTS-dUMP take an open conformation, and raltitrexed binding induces structural changes into a closed conformation in LvTS-dUMP-raltitrexed. Compared to those in other known TS-dUMP-raltitrexed complexes with the closed conformation, the C-terminal loop in LvTS-dUMP-raltitrexed shifts its position away from the bound raltitrexed; the distance between C6 of dUMP and S gamma of the catalytic cysteine is obviously longer than that in the known TS structures with closed conformations, resembling that in the TS structures with open conformations. Other species-specific interactions with dUMP and raltitrexed are also observed. Therefore, LvTS-dUMP-raltitrexed adopts a loosely closed conformation with structural features intermediate between the closed and the open conformations that were reported in other TSs. Our study provides the first crustcean TS structure, and reveals species-specific interactions between TSs and the ligands, which would facilitate designing pathogen-specific TS inhibitors for shrimp-disease control.
Keywordthymidylate synthase (TS) closed conformation deoxyuridine monophosphate (dUMP) thymidine monophosphate (TMP) raltitrexed Litopenaeus vannamei
DOI10.1007/s00343-019-9184-8
Indexed BySCI
Language英语
Funding ProjectNational Natural Science Foundation of China[31572660] ; National Natural Science Foundation of China[31872600] ; 1000 Talents Program ; Qingdao Innovation Leadership Project[18-1-2-12-zhc]
WOS Research AreaMarine & Freshwater Biology ; Oceanography
WOS SubjectLimnology ; Oceanography
WOS IDWOS:000516140400007
PublisherSCIENCE PRESS
Citation statistics
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/165539
Collection实验海洋生物学重点实验室
Corresponding AuthorMa Qingiun
Affiliation1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China
2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao 266000, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Ctr Ocean Megasci, Qingdao 266071, Peoples R China
First Author AffilicationKey Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationKey Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences;  Center for Ocean Mega-Science, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Liu Changshui,Zang Kun,Li Shihao,et al. Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. JOURNAL OF OCEANOLOGY AND LIMNOLOGY,2020:9.
APA Liu Changshui,Zang Kun,Li Shihao,Li Fuhua,&Ma Qingiun.(2020).Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed.JOURNAL OF OCEANOLOGY AND LIMNOLOGY,9.
MLA Liu Changshui,et al."Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed".JOURNAL OF OCEANOLOGY AND LIMNOLOGY (2020):9.
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